Water soluble compounds having vitamin k activity



Patented Juiy 31, 1945 KAO'I'IVITY Bernard. R. Baker, Nanuet, N. Y., assignor to Lederle Laboratories, Inc., New York, N. Y., a

corporation of Delaware No Drawing. Application June 25, 1942, Serial No. 44 494 tholiydroquinone disodium phosphate will be il- This invention relates to water-soluble derivatives of 2-methyI-L4-naphthohydroquinone having anti-hemorrhagic activity, and more particularly relates to monoacyl-z-methyl-l,4-naphthohydroquinone monophosphoric acid esters and salts thereof.

One of the more active anti-hemorrhagic compounds of the vitamin K type is 2-methyl-1A- naphthcquinone, it being very widely used in the treatment of hypo-prothrombinemia, hemorrhagic diathesis of the newly born, post-operative bleeding in jaundice, and persons having prothrombin deficiencies.

The quinone, however, is not entirely satisf tory for all types of administration. For example, it is water-insoluble and cannot be satisfactorily administered parenterally. Furthermore, it is extremely sensitive to light. The 2- methyl-1,4-naphthoquinone may be reduced to the corresponding hydroquinone which is stable to light and which has a satisfactory antihemorrhagic activity. However, the 2-methyl- 1,4-naphthohydroquinone is not water-soluble, andhencecannotbeutilissdinthevrmtion of aqueous parenteral solutions. In the past, aqueoussolutionsofthesodiumbisuliiteaddition compounds of 2-methyl-L4-naphthoqldnone and the mono-glycosides of the correspondinghydroquinonehavebeenusedforparenterai administration. These prior art aqueous solutions are not entirely satisfactory Pr parations, and it is desirable that a satisfactory preparation be provided. One of the disadvantages of the aqueous solutions of the sodium bisulilte addition compounds is that in neutral solutions they cannot be sterilized by heat and must be kept at the obiectionably low pH of 2.5 in order to avoid loss of activity. The mono-glycosides suifer the disadvantages of being difiicult and expensive to prepare and forming somewhat unstable solutions.

In accordance with the present invention it has been found that the hitherto unknown monoacyl-2-methyl-L4 naphthohydroquinone monophosphoric acid esters will form extremely watersoluble salts. These aqueous solutions are essentially neutral. stable under ordinary conditions, andcanbereadilysteriliaedbyheatwithoutloss of anti-hemorrhagic activity. The solutions can be used orally, intrammcularly or intravenously.

, and show approximately the same activity as the sodium bisuliite addition compounds or the mono-glycosides.

A suitable method for preparinga representative compound, rnonoacetyl-2-methyl-iA-naph lustrated in conjunction with the following specific example. It should be understood, however, that the example is given merely by way of illustration and the invention is not to be limited to the details set forth therein.

Monoacetv-Z-methu'l-I,4-naphthohudroquinone disodium phosphate solution in hot butanol followed by cooling to 0 C. The product (1 g.) was obtained as a hygroscopic white powder.

An improvement in yield was obtained by the following procedure. To a mixture of 13 cc. of

phosphorous oxychloride and 20 cc. of pyridine was added dropwise with ice cooling a solution of 20 g. of the monoacetate of 2-methyl-L4-naphthohydroqiunone in 40 cc. of pyridine at such a rate that the temperature was 15-20 C. After thirty minutes at 25 C. the solution was poured on cracked ice and neutralized with 38 g. of anhydrous sodium carbonate, then evaporated'to dryness in vacuo. The gummy sodium saltwas extracted with 300 cc. of hot butanol (100' (3.). and the solvent removed in vacuo. The residue" was dissolved in isopropyl alcohol and on being cooled to 0' C. 81.5 g. (90%) of product caper-,- ated. It was pin'iiied by solution in hot butanol and addition of several volumes of isopropyl aloohol, yield 20 g. (60%).

The monoacetyl-2-methyI-L4-naphthobydroouinone employed in the above process may be conveniently prepared by treating the diacetate of 2-methyl-L4-naphthohydroquinone in methanol with ammonium hydroxide at room temperstore for about twenty-four hours and rea'ystallising from a suitable solvent.

The monoacetyl derivative of 2-methyl-L4- naphthohydroquinone is the preferred monoacyl derivative for carrying out the above reaction because of its cheapness and availabflity. Instead of the monoacetate any other organic monoacyl derivative of 2-methyl-L4-naphthohydroquinone may be employed. Among the suit- Grams l-acetoxy-Z-methyl 4 naphthyl disodium phosphate 8.68 Sodium bisulfite 1.20 Sodium chloride 8.00

Distilled water q. s. to 1000 cc.

The sodium bisulfite is dissolved in the distilled water (about 800 cc.) and the sodium chloride added. After solution is complete the l-acetoxy-2-methy1-4-naphthyl disodium phosphate is dissolved. The solution is adjusted to 1000 cc. volume with distilled water and filtered through a porous glass filter to remove lint. (The glass filter is washed with a solution of 0.12% bisulfite in distilled water prior to filtering the vitamin solution.) The clear, lint-free, colorless liquid is filled in 1 cc. ampules and sterilized by heating at 100 C. for twenty minutes.

It is obvious that the preceding description and examples are intended to be illustrative only and that they may be varied or modified to a considerable extent without departing from the spirit 0! the invention or sacrificing the advantages thereof. I do not, therefore, intend to limit myself to the specific embodiments herein set forth except as indicated in the appended claims.

I claim:

1. An alkali forming metal salt of monoa'cetyl- 2 methyl-1,4-naphthohydroquinone monophosphoric acid ester.

2. The compound monoacetyl-2-methyl-L4- naphthohydroquinone disodium phosphate.

BERNARD R. BAKER. 

